Translating Extinction of Fear to Anxiety Disorder Treatment

将恐惧的消除转化为焦虑症的治疗

• 批准号: 6933921
• 负责人: MARK G BARAD
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-10 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933921
• 关键词: anxiety disorders; behavior test; behavior therapy; behavioral /social science research tag; behavioral extinction; clinical research; combination therapy; cues; data collection methodology /evaluation; electrical conductance; electrodes; electrostimulus; expectancy; fear; heart rate; human subject; human therapy evaluation; interview; laboratory mouse; mental disorder chemotherapy; nonhuman therapy evaluation; obsessive compulsive disorder; operant conditionings; phobias; reflex; yohimbine

DESCRIPTION (provided by applicant): Fear extinction, the reduction of conditional fear by repeated cue (CS) exposure, has long been the explicit model of behavior therapy for human anxiety disorders. The goals of this R21 application are both to strengthen the evidence for this model and to test the translational potential of several recent findings in rodent extinction. In order to better establish the utility of the model of rodent fear extinction, we propose to perform a series of parallel studies in three groups: fear conditioned mice, fear conditioned normal human subjects, and patients with anxiety disorder. We will perform the first comparison to test whether the mechanisms of fear extinction in mice parallel those in fear-conditioned humans. We will perform the second comparison to test whether extinction of conditioned fear in normal human subjects is similar to the extinction of chronic fears in human anxiety disorder patients. We will use this parallel approach in two specific Aims. In Aim 1 we will investigate the role of expectancy in extinction. In fear conditioned humans and mice, we will manipulate the relative lengths of CS used during training and during extinction to create cue presentations that will or will not disconfirm the expectation of an adverse event. In phobic patients, we will use their subjective ratings of expectancy to create such disconfirming or non-disconfirming exposures. Throughout all the human experiments we will monitor both subjective expectancy and physiological variables of heart rate, skin-conductance and eyeblink startle, to seek reliable correlates of disconfirming exposures that effectively generate extinction. In Aim 2 we will investigate the role of excitation in generating extinction. Based on the hypothesis that increased excitation, or fear, during extinction will yield greater extinction, we test both behavioral and pharmacological means of increasing fear. Psychologically, we will increase excitation through compounds of independently conditioned cues in mice and normal human subjects. Pharmacologically, we will use a variety of anxiogenic compounds in mice. Having shown that yohimbine, an anxiogenic alpha2 adrenergic antagonist, accelerates extinction in mice, we will test the effects of yohimbine alone and in combination with the cognitive enhancer, d-cycloserine, in fear-conditioned human beings and anxiety disorder patients. These experiments should help establish the translational validity of the extinction model for anxiety disorder treatment and also may yield potential improvements in current anxiety disorder treatments.

描述（由申请人提供）：恐惧消除，即通过重复提示（CS）暴露来减少条件性恐惧，长期以来一直是人类焦虑症行为治疗的明确模型。 R21 应用的目标是加强该模型的证据，并测试啮齿动物灭绝方面最新发现的转化潜力。为了更好地建立啮齿动物恐惧消退模型的实用性，我们建议分三组进行一系列平行研究：恐惧条件小鼠、恐惧条件正常人类受试者和焦虑症患者。我们将进行第一次比较，以测试小鼠的恐惧消退机制是否与处于恐惧条件下的人类相似。我们将进行第二个比较，以测试正常人类受试者条件性恐惧的消失是否与人类焦虑症患者慢性恐惧的消失相似。我们将在两个特定目标中使用这种并行方法。在目标 1 中，我们将研究预期在灭绝中的作用。在具有恐惧条件的人类和小鼠中，我们将操纵训练期间和灭绝期间使用的 CS 的相对长度，以创建会或不会否定不良事件预期的提示呈现。对于恐惧症患者，我们将使用他们的主观期望评级来创建此类否定性或非否定性暴露。在所有的人体实验中，我们将监测心率、皮肤电导和眨眼惊吓的主观预期和生理变量，以寻找有效产生灭绝的否定暴露的可靠关联。在目标 2 中，我们将研究激发在产生消光中的作用。基于在灭绝过程中增加兴奋或恐惧会导致更大的灭绝的假设，我们测试了增加恐惧的行为和药理学方法。从心理上讲，我们将通过独立条件线索的化合物来增加小鼠和正常人类受试者的兴奋度。在药理学上，我们将在小鼠中使用多种致焦虑化合物。育亨宾（一种引起焦虑的 α2 肾上腺素能拮抗剂）已证明育亨宾会加速小鼠的灭绝，我们将测试育亨宾单独使用以及与认知增强剂 d-环丝氨酸联合使用对患有恐惧条件的人类和焦虑症患者的效果。这些实验应该有助于建立焦虑症治疗消退模型的转化有效性，并且还可能对当前焦虑症治疗产生潜在的改进。